Freeze dry composition and method for oral administration of drugs, biologicals, nutrients and foodstuffs

ABSTRACT

A readily dissolvable carrier material having sufficient rigidity for administration of drugs, nutrients, vitamins, biologically-active materials, foodstuffs and combinations thereof capable of rapid dissolution by saliva, bodily fluids or other liquid comprising an interim skeletal structure of a watersoluble, hydratable gel or foam forming material, preferably a proteinaceous material, such as with maltodextran, in the hydrated state and dehydrated to leave spaces in place of hydration water. On dissolution by saliva, bodily fluids or other liquids, the composition becomes a liquid system. While the oral route is preferred, other routes may be used to administer the compositions of this method.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of copending application Ser.No. 393,582 filed Aug. 14, 1989, now U.S. Pat. No. 5,039,540.

FIELD OF THE INVENTION

The present invention is directed to semi rigid or rigid solid carriershaving a high degree of void space for carrying drugs, biologicallyactive materials, foodstuffs, e.g., nutrients, and any other medicallyuseful materials or materials capable of sustaining human or animallife. More particularly, the present invention is directed to solidmaterials capable of carrying drugs, nutrients and the like, and capableof relatively immediate dissolution into liquid form upon contact withanimal or human saliva or water for oral ingestion. In otherembodiments, the solid carriers of the present invention are dissolvableand/or dispersible in aqueous liquids for liquid administration ofdrugs, nutrients and the like. In any embodiment, the compositions ofthe present invention are promptly available for absorption by mammalsand can be prepared in the form of wafers, tablets, granules, powders orin liquid form for administration to man and animals. In particular, themethods and compositions of the present invention are directed to a newfreeze drying process to dehydrate hydrated gel and foam materials,particularly proteinaceous substances, thereby leaving porous solidmaterials capable of absorbing and adsorbing high percentages of drugs,nutrients, and the like, and capable of rapid dissolution in aqueousliquids or in the mouth of man and animals for prompt delivery of activematerials to the bloodstream.

BACKGROUND OF THE INVENTION AND PRIOR ART

The method and compositions of the present invention are directed to analternative method of drying drug and nutrient carriers that producesolid, rigid, but rapidly dissolvable drug and nutrient carriers capableof rapid liberation of the active component to the body in a method thatyields new and unexpected result over extant methods of freeze drying.

In accordance with an important feature of the present invention, acomposition of (1) a hydrogel or foamed, non-toxic, edible solid carriermaterial, such as a proteinaceous material, particularly gelatin or agelatin derivative, e.g., gelatin; gelatin A; gelatin B, modified fluidgelatin, albumin, and the like; or hydrogels formed from materials suchas acacia, tragatanth, and/or guar gum; or aqueous foams formed with anyanionic, cationic or amphoteric surfactant, either synthetic or natural(biosurfactants) e.g., lecithin, or a lipoprotein, e.g. a phospholipid;together with (2) a non-toxic, edible, polysaccharide, capable ofrigidifying the hydrogel or foam substance during dehydration thereof,for example, dextran or a dextran derivative, such as maltodextran, canbe dried in accordance with the present invention to leave a porousskeleton carrier, preferably of a proteinaceous material, capable ofabsorbing and/or adsorbing many times its weight in a drug and/ornutrient and the like.

In accordance with one important embodiment of the present invention,the solid, porous, skeletal carrier is formed by drying the fullyhydrated gel or foam material from the gel or foamed state by transferof water from the hydrated material to an alcohol solution, when boththe hydrated gel or foam material and the alcohol are frozen or nearfreezing, without necessitating vacuum conditions, as needed forlyophilization.

A literature search of Chemical Abstracts 1975 to 1988 failed to revealany reference which anticipates or suggests the water removal methods ofthis invention or the products produced by such methods.

Reference texts such as Remington's Pharmaceutical Sciences, 15thEdition, 1976, and Lachman et al, The Theory And Practice Of IndustrialPharmacy, Lea & Febiger, 1978, describe the process of lyophilization asa method to stabilize water and heat-sensitive drugs.

Patent references which include lyophilization in their respectivemethods are exemplified by Alexander U.S. Pat. No. 4,573,883; Lafon U.S.Pat. No. 4,616,047; Vendel U.S. Pat. No. 3,496,267 and Saferstein, et alU.S. Pat. No. 4,752,466. In each of these patents a method involvinglyophilizing or freeze drying under vacuum conditions of unstablecompositions is disclosed.

Aside from the common use of low temperature, the low temperature dryingmethod of the present invention has very little similarity to theprocess of lyophilization. The differences of method and product betweenthis invention and the well known lyophilization process will becomemore apparent hereinafter.

Lyophilization involves the use of mechanical equipment and control ofvapor pressure to produce stabilized drugs. In contrast, the method ofthe present invention includes the use of an organic solvent and isbased on the chemical processes of solubilization and dissolution toproduce drug and nutrient delivery compositions, preferably underambient pressure conditions.

SUMMARY OF THE INVENTION

In brief, the present invention is directed to compositions and methodsproviding porous solids and semi-solids that disintegrate virtuallyinstantaneously when contacted by water, saliva, and aqueous solutionsand dispersions and are particularly useful for the oral delivery andingestion of drugs, nutrients and the like. As used in this disclosure,the term "drug" is used to mean any composition defined as a drug by theFood, Drug and Cosmetic Act and its amendments. Also, the terms"nutrients", "foods" and "foodstuffs" are used interchangeably and areused to mean any composition in liquid, solid or semi-solid form,without limit, or combinations thereof that are ingested and assimilatedby an animal, particularly man, to maintain growth and life. Thesecompositions which may be used singly or in any combination inconjunction with the disclosed delivery system include vitamins,minerals, essential and non-essential amino acids, cations, anions; andalso fats, proteins and carbohydrates, without limit, includingnutritive derivatives therefrom. For purposes of this specification,powdered, granular or other forms of beverages such as coffee, milk andthe like are included as "food" compositions that can be prepared by themethod of the present invention.

Finished products of this method may be in the form of wafers, tablets,powders, granules or liquid forms. Alternatively, finished products ofthe present invention in the form of wafers, powders or granules may beused to prepare emulsions and suspensions of drug, biologically active,medical or nutrient components.

On dissolution, the product can become an emulsion, a suspension, asolution, or any combination depending upon the solubility of the activecomponent and the excipients of the dosage form in water or in otherfluids.

In accordance with an important feature of the present invention, themethods of the present invention also produce useful freeze driedcompositions of food and drug compositions that are more stable, andmore capable of dissolution and dispersion than those produced by othermethods.

In accordance with an important feature of the present invention, acomposition of (1) a hydrated gel or foam material and (2) a rigidifyingagent for the gel or foam, is intimately contacted with an anhydrousorganic liquid desiccant, such as anhydrous ethyl alcohol at atemperature of about 0° C. or below, until substantially all of thewater is removed from the gel or foam material. To achieve the fulladvantage of the present invention, a homogeneous mixture of the gel orfoam, together with a rigidifying agent for the gel or foam is immersedin the liquid desiccant until completely dehydrated.

To achieve the full advantage of the present invention, the componentmaterials of the compositions are sequentially combined to produceinterim products that are subjected to processes of solubilization anddissolution at temperatures of about 0° C. or below; preferably -10° C.or lower. An ice-dissolving anhydrous organic desiccant is used fordehydration in accordance with the preferred process of the presentinvention. The organic liquid water removal step removes the water fromthe composition being prepared and provides new and unexpectedadvantages in the finished products. The finished products in accordancewith the method of the present invention are complete when from about50% to about 100% by weight of the water of the hydrated gel or foammaterial of this method have been removed and transferred to the liquiddesiccant.

The water used to make the hydrated gel can be any water, particularlypure water such as distilled water. It has been found that structuredwater that has been polarized, particularly the equilibrium phase waterand/or coacervate phase water from a two phase coacervate watercomposition provide increased structural integrity to the solid carriermaterials and increase production speed. Equilibrium phase water andcoacervate phase water can be obtained by the methods disclosed inEcanow U.S. Pat. No(s). 4,343,797; 4,588,032; 4,596,788; and preferablyEcanow U.S. Pat. No. 4,539,204, which patents are hereby incorporated byreference. Two phase aqueous coacervate compositions having non-misciblewater phases (equilibrium phase water and coacervate phase water) inequilibrium due to their differences in polarity are well known, and anynon-toxic equilibrium phase water and/or coacervate phase water issuitable in accordance with this embodiment of the present invention.Coacervate phase water is preferred because of its ability to impartincreased structural integrity to the solid carriers of the presentinvention while retaining their porosity and prompt dissolutionproperties.

In addition to improving the structural integrity of the watercomposition, i.e. less crumbling during packaging and the like, the useof coacervate phase water as opposed to distilled water to formulate thewafer composition reduces the time necessary to produce the finishedproduct by approximately 10%. Given that anticipated manufacturing runsof the product will be 50,000 wafers or more per week, the savings inprocessing time is believed to be significant.

In this method, the water-hydrated composition of the gel or foammaterial and a rigidifying agent therefor are frozen in a vesselsuitable for maintaining temperatures of 0° C. or lower. The waterremoval steps may be repeated as often as is required to produce therequired degree of dehydration.

To achieve the full advantage of the present invention, the finishedproteinaceous compositions are completely dehydrated. On completion ofthe low temperature desiccant water-removal steps, the resulting productoptionally can be further dried by any of the conventional methods toprovide porous, solid drug, biological and/or nutrient deliverycompositions in the form of wafers, tablets, granules and powders. Ifdesired, the solids can be rehydrated to provide liquid deliverycompositions.

Incorporation of a desired dose of the medical or nutritionalcomponent(s) in the porous solid carriers of the present invention and,as preferred, the addition of one or more flavoring agents complete theprocess of the present invention. The finished compositions are suitablefor oral administration and provide new and unexpected rapid liberationof the active component to the bloodstream of the recipient,particularly for epilingual administration. Since the compositions ofthe present invention disintegrate instantaneously in the mouth of theuser, their contents are promptly available for absorption by the body.The finished products of this invention can be prepared as wafers,tablets, granules, powders, or as required as liquid forms such assuspensions and can be administered to man and animals. The methods andcompositions of the present invention include methods to prepare freezedried foodstuffs, and produce drug formulations that have improvedstability and dispersibility in liquids.

In accordance with an important feature of the present invention, thecompositions of the present invention have several advantages overconventional oral dosage forms: (1) the described formulations overcomeobjectionable tastes of incorporated nutrients and drugs, (2) ascompositions of this invention disintegrate in the mouth or when, as anoption, the formulations are prepared and taken in liquid form, such assuspensions, the compositions retain the characteristics of a stablesuspension, and (3) the medical and nutrient components of thecompositions are quickly available for absorption by the body. Finishedproducts of this invention are ideal for persons who have difficultyingesting drugs, biologically-active materials and nutrients which arecommonly prepared as pills or tablets.

Accordingly, an aspect of the present invention is to provide a new andimproved composition comprising a porous, dehydrated solid carrier fordrugs, biologically-active materials, nutrients, and the like thatdissolves unexpectedly quickly in the mouth of the recipient forunexpectedly fast delivery of an active substance to the bloodstream.

Another aspect of the present invention is to provide a new and improvedmethod of dehydrating a gel or foam solid material in gel or foam formsuch that the gel or foam substantially retains its gelled or foamedvolume, and retains sufficient rigidity for handling and oral ingestion,but loses most or all of its water content to provide a solid, skeletalcarrier that is exceptionally porous, capable of carrying many times itsweight in a liquid active substance and capable of unexpectedly quickdissolution when orally ingested.

Another aspect of the present invention is to provide a new and improvedgelatin-polysaccharide solid carrier, and method of manufacturing thesolid carrier, for oral administration of active materials, such asdrugs, biologically-active materials, foods, nutrients, vitamins and thelike that is unexpectedly porous for receipt of the active material andis unexpectedly readily dissolvable in the mouth with saliva so that theactive material is quickly assimilated through the mouth tissue oringested into the GI tract.

Still another aspect of the present invention is to provide a new andimproved method of freeze drying a hydrated, proteinaceous solid carriermaterial by intimately contacting the carrier, in substantiallycompletely hydrated form, with an anhydrous desiccant, at 0° C. orbelow, to transfer water, in its frozen state, to the desiccant bysublimation or dissolution or solubilization.

The above and other aspects and advantages of the present invention willbe better understood in conjunction with the following detaileddescription.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The finished products of the present invention may be wafers, tablets,granules, powders or liquids. Tablets or wafers weighing about 100 to150 mgs are preferred and may be of any size appropriate for oraladministration. The compositions of this method may also be introducedinto the body by other routes of administration. The disclosed carriercompositions may range in weight from about 1/2 gram to about 1200 mgsor more. The preferred method comprises the following steps: (1) Mix thefollowing ingredients together: about 1 gram of flavored gelatin powderor other gelatin-based equivalent, about 2 grams of maltodextrose, about0.5 gram of gelatin A; about 2 grams of sucrose, optionally forpalatability, and as preferred, about 1 gram, or other desired dosage,of flavoring agents or sweeteners, such as ASPARTANE®. The quantitiesmay be adjusted as preferred by the formulator. After mixing thesecomponents, add coacervate phase water in an amount that will make afinal volume of about 100 ml., (2) heat while stirring the product ofstep (1) to about 60° C. or until the product becomes a visually clearsolution. Next, (3) cool the product of step 2 to about 37° C. or lessbut preferably short of freezing, (4) following step 3, the requiredquantity of the nutrient, drug or other active component is dispersed inthe product of step 3. As preferred, one or more flavoring agents may beadded to the product of step 3 at the same time the drug component hasbeen mixed into the product of step 3 (5). Next, rinse the molds to beused in forming the composition with any pharmaceutically acceptablecoating liquid or lubricant, for example a solution of about 10% of aphospholipid, such as lecithin, in grain alcohol of about 150-190 proof.(6) Allow the molds to dry at ambient temperature. (7) Next, fill eachcompartment of the mold with that quantity of the product of step 4 aswill give the desired unit does in each finished wafer or tablet aspreferred. (8) Store the product of step 7 at a temperature of 0° C. orlower for about 30-60 minutes or until the molded product (e.g. wafer ortablet) is frozen solid. Temperatures of about -20° C. to about -30° C.are preferred. (9) Next, on completion of Step 8, the frozensemi-finished product is removed from the mold.

At the option of the formulator, any one step or combination of processsteps 1 through 8 and the related optional steps may be repeated toproduce a semi finished product comprised of any number of layers aspreferred by the formulator. The frozen tablets are removed from themold and contacted with a suitable anhydrous alcohol, e.g. ethylalcohol, such as by immersion therein, preferably in an airtight(hermetically sealed) container, step (10), as follows: The weight ratioof alcohol to the product can be approximately at least 10:1 alcohol toproduct, but is preferably about 40:1. This ratio may be adjusted asdesired by the formulator. Next, place the product of step 8 in asuitable fluid-permeable container, e.g. a plastic container which maybe a fine mesh plastic bag or a plastic bottle containing multiple holesof 0.5 mm or less or more and immerse in a container of anhydrous ethylalcohol maintained at a temperature of -15° C. or lower. The watercontent of the alcohol can be measured before this step. Step 10continues until the water content of the alcohol is about 2.5% or more.The process of step 9 is repeated using a fresh supply of anhydrousalcohol until about 100% of the water has been removed from the dosageform formulation. Next, optionally, place the tablets or wafersresulting from step 10 on blotting paper and transfer quickly to avacuum chamber. (11) Optionally vacuum dry the product of step 10 atambient temperature until no odor of the ethyl alcohol remains. (12) Adesired quantity of the drug component then is added by means of apipette to the surface of each wafer or tablet after vacuum drying.

Another method is as follows: (1) Mix the following ingredientstogether: about 1 gram of flavored gelatin powder or other gelatin-basedequivalent, about 2 grams of maltodextrose, about 0.5 gram of gelatin A;about 2 grams of sucrose, optionally for palatability, and as preferred,about 1 gram, or other desired dosage, of flavoring agents orsweeteners, such as ASPARTANE®. The quantities may be adjusted aspreferred by the formulator. After mixing these components, adddistilled water in an amount that will make a final volume of about 100ml., (2) heat while stirring the product of step 1 to about 60° C. oruntil the product becomes a visually clear solution. Next, (3) cool theproduct of step 2 to about 37° C. or less but preferably short offreezing, (4) rinse the molds to be used in forming the tablets of thismethod with any pharmaceutically acceptable coating liquid or lubricant,for example a solution of about 10% of a phospholipid, such as lecithin,in 190 proof grain alcohol. (5) Allow the molds to dry at ambienttemperature.

Next, (6) fill each compartment of the mold with about 1 ml of theproduct of step 3. (7) Store the product of step 6 at a temperature of0° C. or lower for about 30 minutes or until the molded product (tablet)is frozen solid. (8) Remove the product of step 7 from storage and addthat quantity of the drug, nutrient or combinations of each, preferablyin powder or liquid form, e.g., as an aqueous solution, as preferred bythe formulator, to the surface of each tablet within the mold. Duringthis step, the product should be protected from thawing. It is preferredthat the product of step 8 is further processed with step (9) whichcomprises the following: remove the product of step 8 from storage andadd from about 0.5 to about 3 mls of the product of step 1 to the uppersurface of each frozen tablet in the mold. (10) Refrigerate the productof step 9 for about 30 minutes or more at 0° C. or lower. At theconclusion of step 10, if preferred, the product is removed fromrefrigeration and one or more flavoring agents are added to the surfaceof each frozen tablet in an amount ranging from a trace amount to onedrop or more according to the preference of the formulator. At thispoint, the product comprises a semi-finished frozen tablet comprising ofthree layers.

At the option of the formulator, any one step or combination of processsteps 1 through 8 and the related optional steps may be repeated toproduce a semi finished product comprised of any number of layers aspreferred by the formulator. On completion of step 10 the frozen tabletsare removed from the mold and contacted with a suitable liquid organicdesiccant, e.g. anhydrous ethyl alcohol, such as by immersion therein,preferably in an airtight container, step (11), as follows: The weightratio of alcohol to the product can be approximately at least 10:1alcohol to product, but is preferably about 30:1 to about 50:1, e.g.about 40:1. This ratio may be adjusted as desired by the formulator.Next, place the product of step 10 in a suitable plastic container whichmay be a fine mesh plastic bag or a plastic bottle containing multipleholes of 0.5 mm or less or more and immerse in a container of anhydrousethyl alcohol maintained at a temperature of -15° C. or lower. The watercontent of the alcohol can be measured before this step. Step 11continues until the water content of the alcohol is about 2.5% to about5% by weight. The process of step 11 is repeated using a fresh supply ofanhydrous alcohol until about 100% of the water has been removed fromthe dosage form formulation. Next, (12) place the tablets resulting fromstep 11 on blotting paper and transfer quickly to a vacuum chamber. (13)Vacuum dry the product of step 11 at ambient temperature until no odorof the ethyl alcohol remains.

In accordance with another important embodiment of the presentinvention, (14) the desired dose of the drug component is added by meansof a pipette to the surface of each tablet after the product has beenvacuum dried.

In accordance with another important embodiment of the present inventionto produce the porous carrier materials, the hydrated composition of gelor foam material and gel or foam material rigidifying agent preferablyin a frozen state, are spread on a preformed sheet. The sheet then isplaced in a suitable freezer chest, preferably manufactured ofporcelain. A container of anhydrous ethyl alcohol also is placed in thefreezer chest in a weight ratio of at least 10:1 alcohol to wet product,e.g., 40:1. The temperature of the interior of the chest is maintainedat the temperature ranging from about 0° C. to about -15° C. or lower.The transfer of water from the starting materials to the alcohol iscontinued until about 90% to about 100% of the solvent is transferredfrom the starting material to the anhydrous ethyl alcohol. The alcoholis replaced as required to complete the process of water removal. Theprocessed material then is removed from the alcohol and dried by anypharmaceutically acceptable method to remove any alcohol which ispresent in the composition. The resulting product comprises a poroussolid suitable for purposes of oral delivery of drugs, nutrients and thelike. The product may be in tablet, powder or granular form, orreconstituted with water or other solvents for a liquid product.

The preferred procedure to add the drug or nutrient component to theporous solid delivery compositions described above is as follows: Thecomponent to be added is dissolved in any appropriate solvent includingorganic solvents. The dissolved drug is added dropwise by means of ahypodermic syringe or other similar device to the surface of thedelivery compositions in that amount that will give the desired dose toeach product unit. The porous solid, its spaces now containing the drugor nutrient, then is dried using any conventional drying method toremove all traces of the solvent used in the formulation step. Aspreferred, the drug or nutrient component can be added to the interimproduct during early stages of preparing the porous solids. As preferredby the formulator, any flavoring agent may be added to the product byplacing the agent in solution and adding that quantity of the flavoringagent that is preferred to the surface of the product by means by ahypodermic syringe or other similar device.

To prepare a granular form of the composition, the finished product isprocessed with a rotating granulator or other similar grindingequipment.

To prepare the powder form of this invention, a fine wire mesh withopenings ranging from about 50 to 300 microns is used in place of theblister mold used to form tablets or wafers. The steps described toproduce the tablet dosage form then are followed to produce a powderdelivery form.

The starting materials of this method comprise the followingcompositions or combinations thereof: any pharmaceutically acceptablegel or foam materials prepared from any surfactant, synthetic orbiological, particularly proteinaceous materials such as gelatin,including types A and B fluid gelatin and gelatin derivatives andalbumin. Other suitable gel or foam forming compounds of biological orsynthetic origin, used singly or in combination, include phospholipids,singly or in combination, particularly lecithin and coacervate egglecithin.

Suitable rigidifying agents for such gels, hydrogels, and foam-formingmaterials include dextran and dextran derivatives, such as maltodextran;carbohydrates including the mono-, di-, and other polysaccharides. Themonosaccharides include without limitation, dextrose, fructose andgalactose and the sugar alcohols mannitol, xylitol and sorbitol; thedisaccharides include without limitation sucrose, lactose and maltose.Oligosaccharides include polymers of the monosaccharide sugars,polysaccharides include dextrans having molecular weights ranging from40,000 to 90,000. The amount of rigidifying agent is an amountsufficient to rigidity the gel or foam material, generally about 0.1 to5 times the weight of the gel or foam forming material (dry basis).

The liquid, anhydrous organic desiccants used for dehydration includeany organic solvent without limitation that will dissolve ice at about0° C. or less, including acetone and the alcohols but especially ethylalcohol about 150 to 200 proof; about 200 proof is preferred. Aspreferred, any pharmaceutically acceptable flavoring agent orcombinations of such agents, including natural and synthetic flavoringagents, such as ASPARTANE®and flavor enhancing agents, such as thecommercial product VELTOL® (Pfizer); preservatives such as methylparaben, propyl paraben and combinations thereof.

The oral delivery compositions of the present invention are useful toadminister drugs in each of the following categories: drugs acting onthe central nervous system; drugs acting at synaptic and neuroeffectorsites; autacoids, cardiovascular drugs; drugs affecting renal functionand electrolyte metabolism; drugs effecting uterine motility; antibioticdrugs; anti-fungal drugs; antineoplastic drugs; drugs acting on bloodand blood forming organs and hormones. Nutrients that are useful fororal delivery in accordance with the present invention includewater-soluble vitamins, such as the B vitamins and vitamin C; watersoluble trace elements such as copper, selenium, calcium, chromium,zinc, magnesium and iron; electrolytes without limitations includingsodium, potassium, magnesium, calcium, lithium, ammonium, phosphorous,chloride, iodide, bromide, fluoride, acetate, sulfate, carbonate,phosphate, lactate, gluconate and lactobionate; also carbohydrates;amino acids including leucine, isoleucine, lysine, methione,phenylalanine, threonine, tryptophan, valine, alanine, arginine,histidine, proline, serine, tyrosine, glycine, taurine and carnitine, asthe L-, D- and racemic forms but particularly the L-acids and branchedchain amino acids; also keto-analogs of all of the above listed aminoacids; partial hydrolysates of proteins and oligo and poly-peptides ofsynthetic origin; also phospholipids without limitation. As an option,antioxidants, preferably a tocopherol, may be included in formulationsof this invention which deliver nutrients.

To prepare freeze dry compositions of food, the following preferredprocess is used. (1) Freeze a unit of the food composition, e.g., wholemilk, at 0° C. or below until the unit is converted into a frozen solid.(2) Next, dehydrate the frozen milk in an airtight container usinganhydrous alcohol preferably in a weight ratio of alcohol to frozen milkof at least about 10:1 to achieve fast dehydration, as follows: Placethe product of step 1 in a suitable fluid-permeable container, e.g. aplastic container which may be a fine mesh plastic bag or a plasticbottle containing multiple holes of 0.5 mm or less and immerse in acontainer of anhydrous ethyl alcohol maintained at a temperature ofabout -15° C. or below. The water content of the alcohol can be measuredbefore this step. Step 2 continues until the water content of thealcohol is about 2.5% or more. The process of step 2 is repeated using afresh supply of anhydrous alcohol. The process continues until about100% of the water (ice) has been removed from the frozen milk. (3) Next,optionally, place the dehydrated frozen milk, e.g., in wafer or tabletform, resulting from step 2 on blotting paper and transfer quickly to avacuum chamber. (4) Optionally vacuum dry the product of step 3 atambient temperature until no odor of the ethyl alcohol remains.Completion of step 4 produces a finished powdered product of freezedried milk, a dry foodstuff. This product has the flavor of the naturalproduct but has improved stability and an extended shelf life extendingto 1 year or more.

To improve the stability and dispersibility of drug formulations, thefollowing process is used. (1) Prepare a slurry of the desired drugusing any liquid as the solvent, i.e., water, glycerin, and the like.Water is preferred, particularly coacervate phase water. In the instanceof water-insoluble drugs, coacervate phase water or a suspension of thedrug in water may be used. (2) Place the composition of step 1 in asuitable fluid-permeable container and follow the procedures of steps 2,3, and 4 described above with reference to the processing of frozenmilk. The finished product comprises the desired drug in powdered formwhich may be placed in liquid or solid form and administered or stored.If packed under vacuum conditions, the shelf life of the drug may extendto 3 years or more.

EXAMPLES EXAMPLE 1

Mix the following ingredients together: 1 gram of flavored gelatinpowder, 2 grams of maltodextran, 0.5 gram of gelatin A; 2 grams ofsucrose and 1 gram of ASPARTANE®. After mixing these components, adddistilled water in an amount that will make a final volume of about 100ml. Stir and heat the product to 60° C.; continue this step until itcomprises a clear solution. Next cool the product to 37° C. Prepareblister molds to make the porous tablets by first rinsing the molds witha 10% solution of lecithin in 190 proof grain alcohol. Following therinsing step, and dry the mold at ambient temperature. Fill eachcompartment in the mold with 3 mls of the solution described immediatelyabove. Next, store the product at a temperature of -10° C. or lower for40 minutes. Remove the product from storage and add 300 mgs of powderedacetominophen to the surface of each tablet within the mold. During thisstep, the product must be protected from thawing. The product is thenstored under refrigeration at -10° C. for 40 minutes.

Next, remove the product from storage and add 3 mls of the gelatin-basedsolution described above to the upper surface of each frozen tablet inthe mold. Refrigerate the product for 40 minutes at -10° C.

Transfer the frozen tablets from the mold to a mesh plastic bag. Immersethe bag and its contents in a hermetically sealed container of anhydrousethyl alcohol maintained at a temperature of -20° C. The immersion stepcontinues until tests reveal that the tablets are completely dehydrated.Replace the alcohol with fresh supplies of anydrous alcohol as requiredto facilitate dehydration. Continue this step until no odor or otherevidence of alcohol can be detected. On completion of this step, thecomposition comprises a finished product.

EXAMPLE 2

Example 2 follows the procedure of Example 1 except that 250 mgs ofpowdered erythromycin is used in place of acetominophen.

EXAMPLE 3

Example 3 follows the procedure of Example 1 except that ASPARTANE® isnot used and the refrigeration temperatures are -20° C. rather than -10°C.

EXAMPLE 4

Example 4 follows the procedure of Example 1 except that all theformulation steps are repeated prior to the immersing the product inanydrous ethyl alcohol. The finished product will comprise a six layertablet.

EXAMPLE 5

The method of Example 1 is followed except that 300 mgs of acetominophenis mixed into the gelatin based solution after it has cooled. The stepof adding acetominophen to the surface of the frozen interin product isomitted.

EXAMPLE 6

The method of Example 1 is followed except that 300 mgs of acetominophenis added to the cooled gelatin-based solution. The finished product ofthis example contains 600 mgs of acetominophen.

EXAMPLE 7

The method of Example 1 is followed except that two drops of cherryflavoring is added by pipette to the surface of each formed tablet.

EXAMPLE 8

The method of Example 1 is followed except that the finished tablets areprocessed by a granulator to produce a granular porous solid dosageform.

EXAMPLE 9

The method of Example 1 is followed except that a fine plastic mesh isused in place of the blister mold. The finished product comprises apowder form of the claimed composition.

EXAMPLE 10

The method of Example 1 is followed except that the following mineralsare added to the cooled gelatin-based solution: iodine 150 mg; calcium,1 mg; magnesium 400 mg; manganese 3 mg; iron 18 mg; copper 2 mg, zink 15mg; and phosphorous, 1 gm. Store the product at 33° C. to give aslurry-like consistency to the product. Following the first freezingstep, a composition comprised of 500 mgs of Vitamin C, 15 units ofVitamin E; 15 mg of Vitamin B₁ ; 17 mg Vitamin B₂ ; 100 mg niacin; 25 mgVitamin B₆ ; 12 mg Vitamin B₁₂, and 25 mg pantothenic acid is added tothe surface of each semi-finished frozen tablet. The remainingprocessing steps of Example 1 are used as given. The step in Example 1in which the drug is added is not used in this Example. In addition,this Example illustrates a method wherein two groups of compositionswhich are incompatible from a manufacturing point of view can beprepared in a single tablet.

EXAMPLE 11

The method of Example 1 is followed except that the step in whichacetominophen is added is not used. In this example, 3.5 grams ofVIVONEX® (Norwich-Eaton) is mixed into the cooling gelatin basedsolution and stored under refrigeration at 35° C. to give a slurry-likeconsistency to the product. The blister molds are filled with 25 mls ofthis composition.

EXAMPLE 12

(1) Mix the following ingredients together: about 1 gram of flavoredgelatin powder or other gelatin-based equivalent, about 2 grams ofmaltodextrose, about 0.5 gram of gelatin A; about 2 grams of sucrose,optionally for palatability, and as preferred, about 1 gram, or otherdesired dosage, of flavoring agents or sweeteners, such as ASPARTANE®.The quantities may be adjusted as preferred by the formulator. Aftermixing these components, add distilled water in an amount that will makea final volume of about 100 ml., (2) heat while stirring the product ofstep 1 to about 60° C. or until the product becomes a visually clearsolution. Next, (3) cool the product of step 2 to about 37° C. or lessbut preferably short of freezing, (4) following step 3, 300 mgs ofacetominophen is dispersed in the product of step 3. As preferred, oneor more flavoring agents may be added to the product of step 3 at thesame time the drug component has been mixed into the product of step 3.(5) Next, rinse the molds to be used in forming the composition with anypharmaceutically acceptable coating liquid or lubricant, for example asolution of about 10% of a phospholipid, such as lecithin, in grainalcohol of about 150-190 proof. (6) Allow the molds to dry at ambienttemperature. (7) Next, fill each compartment of the mold with thatquantity of the product of step 4 that will give the desired unit dosein each finished wafer or tablet as preferred. (8) Store the product ofstep 7 at a temperature of 0° C. or lower for about 30-60 minutes oruntil the molded product (e.g. wafer or tablet) is frozen solid.Temperatures of about -20° C. to about -30° C. are preferred. (9) Next,on completion of step 8, the frozen semi-finished product is removedfrom the mold.

EXAMPLE 13

The method of Example 12 is followed except that equilibrium phase water(in the same amount) from a two-phase coacervate composition issubstituted for distilled water.

EXAMPLE 14

The method of Example 12 is followed except that coacervate phase water(in the same amount) from a two-phase coacervate composition issubstituted for distilled water.

I claim:
 1. A readily dissolvable carrier material having sufficientrigidity for administration of drugs, nutrients, vitamins,biologically-active materials, foodstuffs and combinations thereofcapable of rapid dissolution by saliva comprising a porous skeletalstructure of a water-soluble, hydratable gel or foam forming materialthat has been hydrated with water, rigidified in the hydrated state witha rigidifying agent in an amount, in proportion to the amount of gel orfoam forming material, of about 0.1 to 5 times the weight of foamforming material, dry basis, and dehydrated with a liquid organicsolvent at a temperature of about 0° C. or below to leave spaces inplace of hydration liquid.
 2. The carrier material of claim 1 whereinthe gel or foam material is selected from the group consisting ofgelatin, gelatin A, gelatin B, fluid gelatin, modified fluid gelatin,albumin, and lecithin.
 3. The carrier material of claim 2 wherein therigidifying material is selected from the group consisting of amonosaccharide, a polysaccharide, and combinations thereof.
 4. Thecarrier material of claim 3 wherein the rigidifying material is selectedfrom the group consisting of dextrose, fructose, galactose, mannitol,xylitol, sorbitol, sucrose, lactose, maltose, dextrans, dextranderivatives and combinations thereof.
 5. The carrier material of claim 4wherein the rigidifying agent is maltodextran.
 6. The carrier materialof claim 5 wherein the maltodextran has a weight average molecularweight of about 40,000 to about 90,000.
 7. The carrier material of claim6 wherein the gel or foam material is a proteinaceous material selectedfrom the group consisting of gelatin, gelatin A, gelatin B, fluidgelatin, modified fluid gelatin and mixtures thereof.
 8. The carriermaterial of claim 1 wherein the hydrated gel or foam material has beendehydrated in a frozen state by contact with an organic solvent having afreezing point below 0° C.
 9. The carrier material of claim 8 whereinthe hydrated, frozen gel or foam material is dehydrated by immersing thefrozen proteinaceous material in lower alcohol (C₁ to C₅) at atemperature of 0° C. or below.
 10. A readily dissolvable, orallyadministrable solid, porous material containing a desired dosage of anactive substance selected from the group consisting of a drug, nutrient,vitamin, biologically-active material, foodstuff, and combinationsthereof capable of rapid dissolution when in contact with water orsaliva and capable of delivering the active substance quickly to thebloodstream orally through the mouth tissue or gastrointestinal tract ofan ingester of the material comprising a porous skeletal structureformed by freeze drying with a liquid organic solvent at a temperatureof about 0° C. or below a water-soluble, gel or foam material that washydrated with water, rigidified sufficiently in the hydrated state witha rigidifying agent in an amount, in proportion to the amount of gel orfoam forming material, of about 0.1 to 5 times the weight of foamforming material, dry basis, for handleability of the dried material,containing an effective amount of the active material absorbed oradsorbed within the skeletal structure.
 11. The material of claim 10further including a flavoring agent to mask an undesirable taste of theactive material upon dissolution in the mouth.
 12. The material of claim10 wherein the gel or foam material is a proteinaceous material selectedfrom the group consisting of gelatin, gelatin A, gelatin B, fluidgelatin, modified fluid gelatin, albumin, and lecithin.
 13. The materialof claim 12 wherein the rigidifying material is selected from the groupconsisting of a monosaccharide, a polysaccharide, and combinationsthereof.
 14. The material of claim 13 wherein the rigidifying materialis selected from the group consisting of dextrose, fructose, galactose,mannitol, xylitol, sorbitol, sucrose, lactose, maltose, dextrans,dextran derivatives and combinations thereof.
 15. The material of claim14 wherein the rigidifying agent is maltodextran.
 16. The material ofclaim 15 wherein the maltodextran has a weight average molecular weightof about 40,000 to about 90,000.
 17. The material of claim 16 whereinthe proteinaceous material is selected from the group consisting ofgelatin, gelatin A, gelatin B, fluid gelatin, modified fluid gelatin andmixtures thereof.
 18. The material of claim 10 wherein the hydrated gelor foam material has been dehydrated in a frozen state by contact withan organic solvent having a freezing point below 0° C. at near freezingtemperature.
 19. The material of claim 18 wherein the hydrated, frozengel or foam material is dehydrated by immersing the frozen proteinaceousmaterial in a lower alcohol (C₁ to C₅) at a temperature of 0° C. orbelow.
 20. A method of manufacturing a carrier material havingsufficient rigidity for carrying and administration of an activematerial selected from the group consisting of drugs, nutrients,vitamins, biologically-active compounds, foodstuffs, and combinationsthereof comprising the steps of:(a) freezing a solution comprising awater-soluble gel or foam material and a monosaccharide orpolysaccharide rigidifying agent for said gel or foam material and waterselected from the group consisting of coacervate phase water,equilibrium phase water and mixtures thereof; (b) contacting the frozenmaterial of step (a) with the active material in an amount sufficient tocause the active material to be absorbed or adsorbed within the frozenmaterial; (c) dehydrating the frozen material from step (b) by causingmaterial transfer of water from the frozen material to an organic,liquid solvent while both the frozen material and the organic solventare held at a temperature of about 0° C. or below; and (d) removing theorganic solvent from the dehydrated material resulting form step (c).21. The method of claim 20 further including adding a flavoring materialto the surface of the dehydrated material.
 22. The method of claim 20further including the step of adding a layer of the hydrated compositionof step (a), in liquid form, onto the surface of the frozen compositionresulting from step (a), and freezing the layers together.
 23. Themethod of claim 22 including adding an active material to the frozenmaterial resulting from step (a) prior to the addition of the layer ofliquid composition.
 24. The method of claim 23 further including addingan active material to the frozen material resulting from adding thelayer of liquid over the frozen composition of step (a) either before orafter freezing the added layer.
 25. The method of claim 20 wherein thegel or foam material is a proteinaceous material selected from the groupconsisting of gelatin, gelatin A, gelatin B, fluid gelatin, modifiedfluid gelatin, albumin, and lecithin.
 26. The method of claim 21 whereinthe rigidifying material is selected from the group consisting of amonosaccharide, a polysaccharide, and combinations thereof.
 27. Themethod of claim 26 wherein the rigidifying material is selected from thegroup consisting of dextrose, fructose, galactose, mannitol, xylitol,sorbitol, sucrose, lactose, maltose, dextrans, dextran derivatives andcombinations thereof.
 28. The method of claim 21 wherein the rigidifyingagent is maltodextran.
 29. The method of claim 24 wherein themaltodextran has a weight average molecular weight of about 40,000 toabout 90,000.
 30. The method of claim 20 wherein the hydrated gel orfoam material has been dehydrated in a frozen state by contact with anorganic solvent having a freezing point below 0° C.
 31. The method ofclaim 30 wherein the hydrated, frozen gel or foam material is dehydratedby immersing the frozen gel or foam material in a lower alcohol (C₁ toC₅) at a temperature of 0° C. or below.
 32. A method of manufacturing acarrier material having sufficient rigidity for carrying andadministration of an active material selected from the group consistingof drugs, nutrients, vitamins, biologically-active compounds,foodstuffs, and combinations thereof comprising:(a) freezing a solutioncomprising a water-soluble gel or foam material and a monosaccharide orpolysaccharide rigidifying agent for said gel or foam material andwater; (b) dehydrating the frozen material from step (a) by causingmaterial transfer of water from the frozen material to an organic,liquid solvent while both the frozen material and the organic solventare held at a temperature of about 0° C. or below; (c) removing theorganic solvent from the dehydrated material resulting from step (b);and (d) adding to the carrier material, prior to freezing, an activematerial in an amount sufficient to cause the active material to beabsorbed or adsorbed within the carrier material.
 33. The method ofclaim 32 wherein the water is selected from the group consisting ofcoacervate phase water, equilibrium phase water and mixtures thereof.